Assessment of functional respiratory complaints and related factors in people with hypermobile Ehlers-Danlos syndrome: Cross-sectional study.

BACKGROUND: Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common type of EDS. Apart from joint symptoms, people with hEDS have systemic manifestations as a chronic modification of the breathing pattern (functional respiratory complaints (FRCs)) and mental disorders. However, the prevalence of FRCs, and its relationship with mental disorders, have not yet been estimated for this population. OBJECTIVES: To assess the FRCs, central sensitization, disease perception, depression, and anxiety in people with hEDS from Belgium; and to identify the clustering of FRCs and determine any association with the characteristics assessed for this sample. METHODS: This cross-sectional study assessed socio-demographic characteristics, Nijmegen questionnaire (NQ), Central Sensitization Inventory (CSI), Brief Illness Perception Questionnaire, and the Hospital Anxiety and Depression Scale (HADS) in people with hEDS from Belgium. A two-step cluster analysis was performed to identify clusters according to NQ, and to understand how the other questionnaires are grouped among these clusters. RESULTS: The Spearman correlation coefficients showed that all the outcomes were significantly and positively correlated with each other (p<0.05). Furthermore, 84.9% of the sample had symptoms suggestive of FRCs, and 54.3% had probable anxiety. Three clusters were grouped (no FRCs, mild FRCs, and severe FRCs), with NQ, HADS-D and CSI-part A being the variables that contributed the most. People from cluster of severe FRCs got the worst scores for all the questionnaires. CONCLUSION: FRCs, central sensitization, depression, and anxiety are prevalent comorbidities in people with hEDS. Moreover, those people with FRCs had worse results in the investigated parameters, with depression being the variable that contributed the most to the clusters of FRCs. Consequently, investigating mechanisms for these co-occurring symptom profiles may improve our understanding of pathogenesis and indicate new management strategies to alleviate these symptoms and lead to the development of more effective care for persons with hEDS.

Gender-Related Impact of Sclerostin Antibody on Bone in the Osteogenesis Imperfecta Mouse.

Osteogenesis imperfecta (OI), which is most often due to a collagen type 1 gene mutation, is characterized by low bone density and bone fragility. In OI patients, gender-related differences were reported, but data in the literature are not convergent. We previously observed that sclerostin antibody (Scl-Ab), which stimulates osteoblast Wnt pathway via sclerostin inactivation, improved spine and long-bone parameters and biomechanical strength in female oim/oim mice, a validated model of human type 3 OI. Here, we wanted to highlight the effect of Scl-Ab on male oim/oim bones in order to identify a possible distinct therapeutic effect from that observed in females. According to the same protocol as our previous study with female mice, male wild-type (Wt) and oim/oim mice received vehicle or Scl-Ab from 5 to 14 weeks of age. Clinimetric and quantitative bone parameters were studied using X-rays, peripheral quantitative computed tomography, microradiography, and dynamic histomorphometry and compared to those of females. Contrary to Wt mice, male oim/oim had significantly lower weight, snout-sacrum length, and bone mineral content than females at 5 weeks. No significant difference in these clinimetric parameters was observed at 14 weeks, whereas male oim showed significantly more long-bone fractures than females. Scl-Ab improved bone mineral density and bone volume/total volume ratio (BV/TV) of vertebral body in Wt and oim/oim, without significant difference between male and female at 14 weeks. Male vehicle oim/oim had a significantly lower cortical thickness (Ct.Th) and BV/TV of tibial diaphysis than female and showed a higher number of fractures at 14 weeks. Scl-Ab increased midshaft periosteal apposition rate in such a way that tibial Ct.Th of male oim/oim was not significantly different from the female one at 14 weeks. The number of fractures was lower in male than female oim/oim after 14 weeks of Scl-Ab treatment, but this difference was not significant. Nevertheless, Scl-Ab-treated oim/oim male and female mice remained smaller than the Wt ones. In conclusion, our results highlighted differences between male and female oim/oim at 4 and 14 weeks of age, as well as some male-specific response of cortical bone to Scl-Ab. These gender-related particularities of oim/oim should be considered when testing experimental treatments.

Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice.

In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap-/- mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.

Sclerostin antibody reduces long bone fractures in the oim/oim model of osteogenesis imperfecta.

Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9 weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6 ±â€¯0.3 versus 2.1 ±â€¯0.8 per mouse, p < 0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, p < 0.001), as well as BMD (+28%, p < 0.001), ultimate load (+86%, p < 0.05), plastic energy (+184%; p < 0.05) and stiffness (+172%; p < 0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; p < 0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.

Biologicals in osteoporosis: teriparatide and parathyroid hormone in women and men.

Osteoporosis is characterized by the occurrence of a host of fractures. According to densitometric values, an operational definition for osteoporosis corresponds to a loss of 25% to 30% (-2.5 T-scores) compared with the mean values of bone mineral density of young premenopausal women. For years, research tried to develop drugs to improve the bone mineral density. According to the compounds, antiresorptive agents are able to decrease the fracture rate by about 30% to 70%, and to increase the bone mineral density. However, the agents increasing the most bone mineral density are not necessarily those that influence the most fracture rates. It has been known for years that parathyroid hormone (PTH) administered cyclically is able to increase bone mineral density. Two analogues of PTH have been developed: PTH (1-34) and PTH (1-84). Both of them are able to increase bone mineral density and reduce the rate of vertebral fracture but not of the hip, nor of nonvertebral fractures, the latter at least for PTH (1-84). Their exact place in the armamentarium of therapy of osteoporosis and their best time of administration are not yet definitely settled. New modes of administration (transdermal, intranasal, oral) will probably become available soon. With all the drugs available today and those still in development, it can be hoped that osteoporosis will become a disease of the past.

Zoledronic acid for treatment of Paget's disease of bone.

Paget's disease of bone is characterised by a focal increase in bone resorption and bone formation. This anarchic metabolism leads to disorganised bone, with bone pain, fragility, deformity and compression of the peripheral or CNS according to the involved site. Quality of life of sufferers is dramatically impaired. Symptomatic therapy trends to relieve pain, but cannot seek to prevent other complications. Only 'specific' therapy can fulfil this purpose. Bisphosphonates have become the cornerstone for therapy of Paget's disease in the last 25 years. Progressively stronger bisphosphonates have been launched on the market. The last drug available, zoledronic acid, the most potent of this drug family, can be administered intravenously. It possesses a long-acting efficacy, allowing a follow up on a yearly basis and permitting the chance of a very long remission of the Pagetic lesion. In the long term, prevention of severe complications can be envisaged, with a reasonable pharmacoeconomic cost.